Restored nitric oxide bioavailability reduces the severity of acute-to-chronic transition in a mouse model of aristolochic acid nephropathy

Aristolochic Acid (AA) nephropathy (AAN) is a progressive tubulointerstitial nephritis characterized by an early phase of acute kidney injury (AKI) leading to chronic kidney disease (CKD). The reduced nitric oxide (NO) bioavailability reported in AAN might contribute to renal function impairment and progression of the disease. We previously demonstrated that L-arginine (L-Arg) supplementation is protective in AA-induced AKI. Since the severity of AKI may be considered a strong predictor of progression to CKD, the present study aims to assess the potential benefit of L-Arg supplementation during the transition from the acute phase to the chronic phase of AAN. C57BL/6J male mice were randomly subjected to daily i.p. injections of vehicle or AA for 4 days. To determine whether renal AA-induced injuries were linked to reduced NO production, L-Arg was added to drinking water from 7 days before starting i.p. injections, until the end of the protocol. Mice were euthanized 5, 10 and 20 days after vehicle or AA administration. AA-treated mice displayed marked renal injury and reduced NO bioavailability, while histopathological features of AAN were reproduced, including interstitial cell infiltration and tubulointerstitial fibrosis. L-Arg treatment restored renal NO bioavailability and reduced the severity of AA-induced injury, inflammation and fibrosis. We concluded that reduced renal NO bioavailability contributes to the processes underlying AAN. Furthermore, L-Arg shows nephroprotective effects by decreasing the severity of acute-to-chronic transition in experimental AAN and might represent a potential therapeutic tool in the future.

马兜铃酸（Aristolochic Acid, AA）相关性肾病（AAN）是一种进展性肾小管间质性肾炎，以急性肾损伤（acute kidney injury, AKI）早期阶段进展为慢性肾病（chronic kidney disease, CKD）为特征。已有研究显示，AAN患者体内一氧化氮（nitric oxide, NO）生物利用度降低，这可能参与肾功能损伤与疾病进展过程。本课题组既往研究证实，补充L-精氨酸（L-arginine, L-Arg）对AA诱导的AKI具有保护作用。鉴于AKI的严重程度可作为CKD进展的强预测因子，本研究旨在评估在AAN从急性期向慢性期的转化阶段补充L-Arg的潜在获益。
实验选用C57BL/6J雄性小鼠，随机分为两组，每日分别接受腹腔内（intraperitoneal, i.p.）注射溶媒或AA，连续给药4天。为明确AA诱导的肾损伤是否与NO生成减少相关，我们在腹腔注射开始前7天起，直至整个实验方案结束，向小鼠饮用水中添加L-Arg。分别于溶媒或AA给药后的第5、10和20天对小鼠实施安乐死。
结果显示，AA处理组小鼠出现显著肾损伤，肾脏NO生物利用度降低，且成功复现AAN的组织病理学特征，包括间质细胞浸润与肾小管间质纤维化。L-Arg治疗可恢复肾脏NO生物利用度，并减轻AA诱导的肾损伤、炎症反应及纤维化程度。
本研究表明，肾脏NO生物利用度降低参与了AAN的核心发病进程。此外，L-Arg可通过减轻实验性AAN急性期向慢性期的转化程度发挥肾保护作用，未来或可成为AAN潜在的治疗干预手段。